Field of the Invention
The present invention relates generally to delivery of therapeutic agents, such as chemically modified oligonucleotides, and more specifically to agents associated with nanotransporters to form a delivery complex, and methods of making and using such complexes for targeted delivery of agents to cells.
Background Information
RNA interference (RNAi) is the process whereby double-stranded RNA (dsRNA) induces the sequence-specific degradation of homologous mRNA. Although RNAi was first discovered in Caenorhabditis elegans, similar phenomena had been reported in plants (post-transcriptional gene silencing [PTGS]) and in Neurospora crassa (quelling). It has become clear that dsRNA-induced silencing phenomena are present in evolutionarily diverse organisms, e.g., nematodes, plants, fungi and trypanosomes. Biochemical studies in Drosophila embryo lysates and S2 cell extracts have assisted to unravel the mechanisms by which RNAi works.
Although RNAi has proven to have tremendous potential as a new therapeutic strategy, there remains a need for RNAi agents that are optimized for use in vivo as well as in vitro. Another goal is to efficiently deploy therapeutic RNAi agents to specifically targeted sites or tissues. Accordingly, delivery systems that allow for target delivery to specific cell types and which are non-toxic, non-immunogenic and biodegradable are needed.
MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by binding with imperfect complementarity in 3′ untranslated regions (3′-UTR) of their target messenger RNAs (mRNAs). mRNAs are 18-25 nucleotide single-stranded small RNAs associated with a complex of proteins, which are called RNA-induced silencing complex (RISC)-like ribonucleoprotein particle (miRNP). This complex inhibits translation or, depending on the degree of Watson-Crick complementarity, induces degradation of target mRNAs. These small RNAs are usually generated from non-coding regions of many gene transcripts and function to suppress gene expression by translational repression. mRNAs have been shown to play important roles in development, cell growth, and differentiation. Recent studies have highlighted the role of miRNAs in various disease states and in regulating host-pathogen interactions. For example, mRNAs have been implicated in cardiovascular disease, inflammation, viral infections, and cancers. Hence, disease-associated miRNAs could become potential targets for therapeutic intervention.